Biological receptors, types

Among the difficult (and sometimes referred to as sensitive ) chromatographic separations, those of enantiomeric antipodes and racemic mixtures are of particularly great importance and of the highest interest. This is because many compounds with a therapeutic effect (and incomparably more often the synthetic species than the natural ones) appear in a clearly defined enantiomeric form and for reasons of safety, need to be isolated from their opposite counterparts. Most phar-macodynamically active compounds are equipped with polar functionalities that make them interact with biological receptors and with the other constituents of a biological environment, and it often happens that these functionahties are of the AB type. In such cases, it can be justly concluded that an almost proverbial difficulty... 

The IL-ls induce their characteristic biological activities by binding to specific cell surface receptors present on sensitive cells. Two distinct receptors, type I and II, have been identified. Both IL-la and IL-ip can bind both receptors. The type I receptor is an 80 kDa transmembrane glycoprotein. It is a member of the IgG superfamily. This receptor is expressed predominantly on fibroblasts, keratinocytes, hepatocytes and endothelial cells. The type II receptor is a 60 kDa transmembrane glycoprotein, expressed mainly on B-lymphocytes, bone marrow cells and polymorphonuclear leukocytes. It displays a very short (29 amino acid) intracellular domain,... 

Fig. 9.8 Examples of rule-of-three compliant molecules that have biological activity better than 10 nM. Under each molecule, the following information is included molecule name, MW, ClogP, the biological activity type, value and target. Target names are as follows D3 and D4 - dopaminergic receptor types 2 and 3 AChE and BChE - acetyl- and butyryl-choline esterases PRa and PRb - progesterone receptor types A and B H] and H3, histamine receptor types 1 and 3 5-HT2a, 5-HT2b, 5-HT2c, 5-HT3, 5-HT4 - serotonin receptor subtypes 2A, 2B, 2C, and types 3 and 4 DAT, NET, 5-HTT - dopamine, norepinephrine and serotonin transporter proteins /X], /x.2, S, ki, ks - opioid receptor types mu-1, mu-2, delta, kappa-1 and kappa-3 5a-Rl and 5o -R2 - 5-alpha-reductase isozymes 1 and 2 Flt-1-fms-like tyrosine kinase receptor.

The TGF- Ss exert their biological actions by binding to specific receptors, of which there are three types (I, II and III). All are transmembrane glycoproteins. All three TGF-)Ss bind to all three receptor types, although they bind with higher affinity to types I and II receptors (53 kDa and 65 kDa, respectively). The intracellular domains of the type I and II receptors display endogenous serine/threonine protein kinase activity. 

Most neurotrophin-sensitive cells express two receptor types on their surface a high-affinity receptor, which appears to mediate most/all of the biological actions of the neurotrophins, and a low-affinity receptor. The high-affinity receptors are all members of a family of tyrosine kinases (the Trks). They are similar to the receptors of many other growth factors, but are expressed almost exclusively on neuronal tissue. 

Histamine exerts its biologic actions by combining with specific cellular receptors located on the surface membrane. The four different histamine receptors thus far characterized are designated H -H4 and are described in Table 16-1. Unlike the other amine transmitter receptors discussed previously, no subfamilies have been found within these major types, although different splice variants of several receptor types have been described. 

Bi receptors may also be important in long-lasting kinin effects such as collagen synthesis and cell multiplication. By contrast, B2 receptors have a widespread distribution that is consistent with the multitude of biologic effects that are mediated by this receptor type. B2 receptors belong to the G protein-coupled family of receptors. Receptor binding sets in motion multiple signal transduction... 

Differences in structure-function and signal transduction of particular receptor types represent major challenge to understand the role of GPCRs in cells and pharmaceutical treatment. Elucidation of these differences and their mechanisms will greatly advance receptor biology, pharmacology and therapeutics. 

In order to form a crystal, molecules must aggregate in an orderly manner. This implies that intermolecular interactions have occurred in specific ways. It therefore follows that the crystal structure per se contains information on preferred modes of binding between the molecules in the crystalline state. In this Chapter we show how information on the most likely stereochemistries of interactions between functional groups in different molecules can be extracted from the three-dimensional coordinates of atoms listed in reports of crystal structure determinations. Three-dimensional structural data on binding stereochemistry may also be obtained from X-ray diffraction studies of the binding of small molecules to crystalline proteins and other macromolecules. These two types of information can be used, for example, to predict how drugs will interact with their biological receptors. 

Biological receptors can include chemically and genetically modifled enzymes, new types of antibodies with high afiinity and selectivity for small molecules, natural or artiflcial receptors or complex biological recognition elements. 

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